DESCRIPTION: (Applicant's Abstract) Comorbidity of cocaine dependence and major depressive disorder (MDD) poses an important clinical challenge. The relatively high incidence of such comorbidity and a variety of previous investigations raise intriguing questions about neurobiological connections between these disorders. We will use positron emission tomography (PET) of human brain metabolism, before and after treatment of the comorbid disorders, as a window into such neurobiological relationships. Our team combines expertise in advanced functional brain imaging with experience in the diagnosis and treatment of comorbid MDD and cocaine dependence. Subjects for this study will be carefully screened volunteers in four samples: cocaine-dependent (CD) only, MDD alone, CD comorbid with MDD, and normal controls. Equal numbers of males and females will be recruited to assess gender differences. The MDD and CD+MDD groups will be treated for 12 weeks with venlafaxine, an antidepressant which our pilot data indicates is effective in the comorbid population. Specific hypotheses about the profile of cerebral metabolism in these groups will be examined as follows: 1) at baseline in all groups, 2) following treatment, when baseline and post-treatment scans will be compared to identify brain sites potentially involved in treatment effects, and 3) following treatment, when baseline scans for responders and non-responders in each treatment group will be correlated with treatment outcome to identify pre-treatment metabolic features which predict responsiveness. We will apply advanced quantitative procedures for examining global, regional, and "network" brain metabolism, and will correlate these measures with standardized measures of treatment success. This methodologic rigor will contribute to understanding the pathophysiology and treatment of patients with comorbid depression and cocaine dependence.